U.S. military veterans are more frequently diagnosed with post-traumatic stress disorder (PTSD) and alcohol use disorder (AUD) than the general population, and individuals with PTSD often self-medicate with alcohol in amounts that worsen health outcomes (e.g., pain), leading to a huge health and financial burden in the United States. Pain is highly co-morbid with PTSD and AUD, but strategies are not adequate for treating individuals living with two or more of these diagnoses, and the neurobiological mechanisms underlying these disorders are not well defined. The ultimate goal of the work proposed here is to improve Veteran health and quality of life by guiding therapeutic strategies that reduce pain in individuals with PTSD and/or AUD. This project falls within the scope of the V.A. Office of Research and Development Biomedical Laboratory Research and Development (BLR&D) Service goal to fund preclinical biomedical and behavioral studies of disorders important for Veteran health. More specifically, this innovative and clinically relevant application proposes work that will examine the neurobiological mechanisms of increased pain sensitivity in individuals that have endured traumatic stress or are dependent on alcohol. This work has clear potential to lead to significant advances in health care for Veterans. This application proposes the use of rodent models to examine the role of brain melanocortin-4 receptor (MC4R) signaling in hyperalgesia/allodynia in individuals that are alcohol-dependent or have been traumatically stressed. We will use behavioral pharmacology techniques to test the therapeutic potential of intra-nasally delivered MC4R antagonists for reducing pain, relative to systemic morphine (the clinical gold standard). We will also use optogenetics and molecular biology techniques to identify the brain circuitry that mediates hyperalgesia/allodynia induced by alcohol dependence and traumatic stress, as well as the circuitry that mediates pain reduction by MC4R antagonists. This question is timely and important because PTSD and AUD are highly co-morbid with each other and with pain disorders, and alcohol is often used as a self-medication strategy to reduce PTSD symptoms and pain. The overall goals of the proposed work are to 1) test the translational potential of intra-nasal delivery of melanocortin receptor drugs for reducing pain in individuals with PTSD and AUD, and 2) identify the brain circuitry that mediates higher pain sensitivity after alcohol dependence or traumatic stress, as well as the circuitry that mediates pain reduction by melanocortin receptor drugs.